Differentiated Thyroid Cancer in Adolescents: Single Center Experience and Considerations for Surgical Management and Radioiodine Treatment

Objective: Differentiated thyroid cancer (DTC) in adolescents rare but with a favorable outcome, despite higher rates of cervical lymph node and pulmonary metastasis compared to adults. The aim of this study was to critically evaluate treatment of adolescents with DTC at a single center. Methods: Patients receiving postoperative radioiodine treatment (RAIT) for DTC between 2005 and 2020 at our institution were screened to identify adolescents according to the World Health Organization definition (10-19 years of age). Demographics, clinico-pathological characteristics, treatment and outcome were analyzed. Results: Among 1,897 DTC patients, 23 (1.3%) were adolescents with a median (range) age of 16 (10-18) years. The female to male ratio was 3.6:1. Sixty percent had classic papillary thyroid cancer, with follicular variant in 40%, which was higher than previously reported (15-25%) for this age group. pT-status was pT1 in 9 (39.2%), pT2 in 8 (34.8%), pT3 in 3 (13%) and pT4 in 3 (13%) patients. In 19 (82.6%) patients, central lymphadenectomy was performed and metastasis was seen in 57%. All patients received RAIT with initial activities of 1.2 (n=1, 4.3%), 2 (n=12, 52.2%) or 3.7 GBq (n=10, 43.5%). Eighteen (78.2%) patients were free of biochemical and radiologic disease at a median follow-up of 60.7 months. Second-line surgery for lymph node relapse was necessary in 3 (13%) cases. There was one disease-associated death. Conclusion: Despite high rates of metastasis, most patients were cured, and second-line surgery was rarely required. Further prospective studies are needed to determine whether less aggressive surgical management or omitting adjuvant RAIT are feasible in patients with limited stages at diagnosis.

Prognostic value of the Weiss and Wieneke (AFIP) scoring systems in pediatric ACC - a mini review.

Histopathological differentiation in pediatric adrenocortical carcinoma (pACC) is difficult and clinical prediction and stratification scores are not evaluated yet. Therefore, this review aims to summarize current evidence on the value and accuracy of the two commonly used scoring systems (Weiss/Armed Forces Institute of Pathology (AFIP)) pACC. On this base, one might be able to evaluate if patients may benefit from a unique scoring system. For this, we performed a systematic review of the published literature and included 128 patients in our analysis. The majority (72%) of the pACCs had a good clinical course. The follow-up time ranged from 0 to 420 months with a mean age of 5.6 years at diagnosis. Patients with a good clinical course were younger (mean 4.8 years) than patients with a poor outcome (mean 7.6 years). Comparing the two scoring systems, the specificity of the Weiss score was very low (25%), whereas the sensitivity was 100%. According to the AFIP score, specificity (77%) was higher than the Weiss score, whereas the sensitivity of the AFIP score was minimal lower with 92%. Age differences were recognizable as the specificity was lower in infants <4 years (20%) than in older children (32%). In contrast, the specificity of the AFIP score was higher in infants <4 years (82%) than in older age groups (76%). Summarizing our results, we could show that the Weiss score is not a suitable tool for the prediction of malignancy in pACC in comparison with the AFIP score, but further efforts may seek to ensure early and accurate stratification through augmented scoring.

Assessment of prognostic factors in pediatric adrenocortical tumors: a systematic review and evaluation of a modified S-GRAS score.

Objective: Pediatric adrenocortical carcinoma (pACC) is rare and prognostic stratification remains challenging. We summarized the clinical prognostic factors of pACC and determined the prognostic value of the pediatric scoring system (pS-GRAS) in adaption to the recommendation (S-GRAS) of the European Network for the Study of Adrenal Tumors for the classification of adult ACC. Design: Analysis of pACC patients of 33 available retrospective studies in the literature. Methods: We searched the PubMed and Embase databases for manuscripts regarding pACC. The pS-GRAS score was calculated as a sum of tumor stage (1 = 0; 2-3 = 1; 4 = 2 points), grade (Ki67 index/rate of mitosis 0-9%/low = 0; 10-19%/intermediate = 1; ≥20%/high = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3 points), age (<4 years = 0; ≥4 years = 1 point), hormone-related symptoms (androgen production = 0; glucocorticoid/mixed/no hormone production = 1 point) generating 10 scores and 4 groups (1: 0-2, 2: 3-4, 3: 5, 4: 6-9). The primary endpoint was overall survival (OS). Results: We included 733 patients. The median age was 2.5 years and >85% of pACC showed hormone activity (mixed 50%, androgen 29%, glucocorticoid 21%). Androgen production was associated with a superior OS. Increasing age correlated with higher rates of inactive or only glucocorticoid-producing tumors, advanced tumor stage, and case fatality. Especially infants < 4 years showed more often low-risk constellations with an increased OS for all tumor stages. The pS-GRAS score correlated with clinical outcome; median OS was 133 months (95% CI: 36-283) in group 1 (n = 49), 110 months (95% CI: 2.9-314) in group 2 (n = 57), 49 months (95% CI: 5.8-278) in group 3 (n = 18), and 16 months (95% CI: 2.4-267) in group 4; (n = 11) P < 0.05). Conclusion: The pS-GRAS score seems to have a high predictive value in the pACC patients, may serve as a helpful tool for risk stratification in future studies, and should be evaluated prospectively in an international context.

Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature.

Background and purpose: Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods: We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results: We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70% female); 78% of patients presented with hormonal activity. RT was mostly performed for curative intent (78%). 88% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64% of the patients died of disease, with 33% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions: Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.

Adrenocortical Carcinoma in Childhood: A Systematic Review.

Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89%). Most patients were diagnosed with localized disease, whereas 23% had metastasis at primary diagnosis. Only 72% of the patients achieved complete resection. In 334 children (23%), recurrent disease was reported: 81%-local recurrence, 19% (n = 65)-distant metastases at relapse. Patients < 4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies.

Mesenchymal Neuroblastoma Cells Are Undetected by Current mRNA Marker Panels: The Development of a Specific Neuroblastoma Mesenchymal Minimal Residual Disease Panel.

Patients with neuroblastoma in molecular remission remain at considerable risk for disease recurrence. Studies have found that neuroblastoma tissue contains adrenergic (ADRN) and mesenchymal (MES) cells; the latter express low levels of commonly used markers for minimal residual disease (MRD). We identified MES-specific MRD markers and studied the dynamics of these markers during treatment. PATIENTS AND METHODS: Microarray data were used to identify genes differentially expressed between ADRN and MES cell lines. Candidate genes were then studied using real-time quantitative polymerase chain reaction in cell lines and control bone marrow and peripheral blood samples. After selecting a panel of markers, serial bone marrow, peripheral blood, and peripheral blood stem cell samples were obtained from patients with high-risk neuroblastoma and tested for marker expression; survival analyses were also performed. RESULTS: PRRX1, POSTN, and FMO3 mRNAs were used as a panel for specifically detecting MES mRNA in patient samples. MES mRNA was detected only rarely in peripheral blood; moreover, the presence of MES mRNA in peripheral blood stem cell samples was associated with low event-free survival and overall survival. Of note, during treatment, serial bone marrow samples obtained from 29 patients revealed a difference in dynamics between MES mRNA markers and ADRN mRNA markers. Furthermore, MES mRNA was detected in a higher percentage of patients with recurrent disease than in those who remained disease free (53% v 32%, respectively; P = .03). CONCLUSION: We propose that the markers POSTN and PRRX1, in combination with FMO3, be used for real-time quantitative polymerase chain reaction-based detection of MES neuroblastoma mRNA in patient samples because these markers have a unique pattern during treatment and are more prevalent in patients with poor outcome. Together with existing markers of MRD, these new markers should be investigated further in large prospective studies.

Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed.

BACKGROUND: Ganglioneuroma (GN) and ganglioneuroblastoma intermixed (GNBI) are mature variants of neuroblastic tumors (NT). It is still discussed whether incomplete resection of GN/GNBI impairs the outcome of patients. METHODS: Clinical characteristics and outcome of localized GN/GNBI were retrospectively compared to localized neuroblastoma (NB) and ganglioneuroblastoma-nodular (GNBN) registered in the German neuroblastoma trials between 2000 and 2010. RESULTS: Of 808 consecutive localized NT, 162 (20 %) were classified as GN and 55 (7 %) as GNBI. GN/GNBI patients presented more often with stage 1 disease (68 % vs. 37 %, p < 0.001), less frequently with adrenal tumors (31 % vs. 43 %, p = 0.001) and positive mIBG-uptake (34 % vs. 90 %, p < 0.001), and had less often elevated urine catecholamine metabolites (homovanillic acid 39 % vs. 62 %, p < 0.001, vanillylmandelic acid 27 % vs. 64 %, p < 0.001). Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001). Complete tumor resection was achieved at diagnosis in 70 % of 162 GN and 67 % of 55 GNBI, and after 4 to 32 months of observation in 4 GN (2 %) and 5 GNBI (9 %). Eleven patients received chemotherapy without substantial effect. Fifty-five residual tumors (42 GN, 13 GNBI) are currently under observation (median: 44 months). Five patients (3 GN, 2 GNBI) showed local progression; all had tumor residuals > 2 cm. No progression occurred after subtotal resection. Two patients died of treatment, none of tumor progression. CONCLUSIONS: GN/GNBI account for one quarter of localized NT and differ from immature tumors in their clinical features. Chemotherapy is not effective. Subtotal resection appears to be a sufficient treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers - NB97 (NCT00017225; registered June 6, 2001); NB2004 (NCT00410631; registered December 11, 2006).

Neuroblastoma messenger RNA is frequently detected in bone marrow at diagnosis of localised neuroblastoma patients.

INTRODUCTION: The clinical importance of the detection of neuroblastoma messenger RNA (mRNA) in bone marrow (BM) of localised neuroblastoma patients at diagnosis remains unclear. In this prospective multicentre study, BM samples of a large cohort, were studied using real-time quantitative polymerase chain reaction (qPCR). METHODS: BM samples at diagnosis from 160 patients with localised neuroblastoma were prospectively collected at Dutch and German centres between 2009 and 2013. qPCR was performed using five neuroblastoma specific markers. The association with other biological factors and the prognostic impact of BM positivity and clinical response was assessed. RESULTS: In 58 out of 160 patients neuroblastoma mRNA was detected in BM. In 47 of the 58 positive samples only one marker was found positive. BM positivity was significantly associated with MYCN amplification (p = 0.02) and deletion of chromosome 1p (p = 0.04). In total 31 patients had an event, of which only five patients had progression to stage IV. BM positivity was not associated with an unfavourable outcome. However, the detection of more than one marker was associated with an unfavourable outcome (systemic or local relapse) (event free survival 48% versus 85%; p = 0.03) in the whole cohort and in the observation group. CONCLUSIONS: BM positivity was associated with unfavourable biological factors and might represent more aggressive tumours. Patients with qPCR positive BM should not be upstaged, because of very few systemic events in the cohort. However, for patients with more than one marker positive a more careful follow-up is advisable. These results need to be verified in a very large cohort of localised patients.

Minimal residual disease detection in autologous stem cell grafts from patients with high risk neuroblastoma.

BACKGROUND: The clinical significance of minimal residual disease (MRD) detected by real-time quantitative PCR (qPCR) in autologous stem cell grafts in high risk neuroblastoma is still controversial. In this retrospective multicenter study, autologous stem cell grafts of a large cohort were studied using a panel of RNA markers. PROCEDURE: From 104 patients with high risk neuroblastoma, who received autologous stem cell transplantation as first line treatment, 66 peripheral blood stem cells (PBSC) and 38 CD34+ selected grafts were retrospectively collected at 2 Dutch and 12 German centers between 1997 and 2010. To investigate graft contamination qPCR was performed by using 5 neuroblastoma specific markers (PHOX2B, TH, DDC, CHRNA3, and DBH). RESULTS: In PBSC 6/66 (9%) and in CD34+ selected grafts 3/38 (8%) samples were contaminated. Graft contamination was not associated with an unfavorable outcome (5-years OS, 66% vs. 50.5%; P=0.6 and 5-years EFS, 22% vs. 35%, P=0.7). In multivariate Cox analysis BM MRD at time of harvest was significantly associated with survival (P=0.008 OS and P=0.002 EFS), but graft contamination was still not associated with an unfavorable outcome (P=0.9 OS and P=1 EFS). CONCLUSIONS: Graft contamination is very infrequent in this retrospective cohort of patients with no or minimal BM disease prior to stem cell collection and does not influence outcome in univariate and multivariate analysis. The presence of MRD at time of harvest is a strong outcome predictor. However, these results will have to be verified in a large prospective study.

Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study.

PURPOSE: Radioiodinated metaiodobenzylguanidine ((123)I-mIBG) scintigraphy is an established imaging method in neuroblastoma. Semiquantitative scoring systems have been developed to assess the extent of disease and response to chemotherapy. We present the results of the comparison between the SIOPEN [International Society of Pediatric Oncology Europe Neuroblastoma Group] score and the modified Curie score. PATIENTS AND METHODS: We retrospectively analyzed 147 mIBG scans of 58 patients older than 1 year of age with stage 4 neuroblastoma from German Neuroblastoma Trial NB97 that were assessed according to the SIOPEN and the Curie scoring method. mIBG examinations were performed at diagnosis and after four and six cycles of chemotherapy. RESULTS: Scoring results were highly correlated between both methods, and interobserver reliability was excellent. A Curie score ≤ 2 and a SIOPEN score ≤ 4 (best cutoff) at diagnosis were correlated to significantly better event-free and overall survival compared with higher scores. After four cycles of chemotherapy, overall survival was significantly better for mIBG-negative patients compared with those with any residual mIBG-positive metastases. After six cycles of chemotherapy, there was no difference in survival between mIBG-negative patients and patients with residual mIBG-positive metastases. Patients without mIBG-positive metastases after four and six cycles of chemotherapy had a better overall survival, but late clearance of mIBG-positive metastases did not improve outcome. CONCLUSION: Higher mIBG scores at diagnosis and occurrence of any residual mIBG-positive metastases after four cycles of chemotherapy predicted unfavorable outcome for patients with stage 4 neuroblastoma. Later clearance of metastases did not improve prognosis. The Curie and the SIOPEN score were equally reliable and predictive.

Prognostic impact of gene expression-based classification for neuroblastoma.

PURPOSE: To evaluate the impact of a predefined gene expression-based classifier for clinical risk estimation and cytotoxic treatment decision making in neuroblastoma patients. PATIENTS AND METHODS: Gene expression profiles of 440 internationally collected neuroblastoma specimens were investigated by microarray analysis, 125 of which were examined prospectively. Patients were classified as either favorable or unfavorable by a 144-gene prediction analysis for microarrays (PAM) classifier established previously on a separate set of 77 patients. PAM classification results were compared with those of current prognostic markers and risk estimation strategies. RESULTS: The PAM classifier reliably distinguished patients with contrasting clinical courses (favorable [n = 249] and unfavorable [n = 191]; 5-year event free survival [EFS] 0.84 +/- 0.03 v 0.38 +/- 0.04; 5-year overall survival [OS] 0.98 +/- 0.01 v 0.56 +/- 0.05, respectively; both P < .001). Moreover, patients with divergent outcome were robustly discriminated in both German and international cohorts and in prospectively analyzed samples (P